1. Field of the Invention
The present invention generally relates to compositions and methods for improving cardiovascular health. In particular, to such compositions and methods comprising delivering a selection of amino acids, plant-derived stanols and sterols, isoflavones, and low glycemic carbohydrates and medium chain fatty acids to the elderly.
2. Description of the Related Art
As the population ages, and in particular as the “baby boomers” grow into their old age, the health problems associated with aging grow increasingly important. This is particularly true in a health system such as the current one where health care costs are distributed across the population; the increased prevalence of aging-related health problems will result in generally increased costs. In addition, reactive health care is more expensive than preventative health care; for example, fixing bones or replacing a hip after a fall by a frail patient is more expensive than preventing that fall by decreasing the patient's frailty. For these and other reasons, it is desirable to have effective, relatively inexpensive means for preventing and ameliorating health problems pervasive in the aged population.
Cardiovascular disease and its related complications, such as stroke and myocardial infarction, are believed to be the current number one cause of mortality within the United States. The development of cardiovascular disease is thought to be due to atherosclerotic plaque formation within both large and small blood vessels. Plaque formation is due to many influences, including increased plasma lipids such as low-density lipoproteins (LDL) cholesterol, very low-density lipoproteins (VLDL) cholesterol, and triglycerides (TG). Recently, the metabolic syndrome of combined hypertension, altered cholesterol, and insulin resistance has been recognized. Studies have shown that 20-30% percent of the United States population has this configuration of metabolic abnormalities.
High circulating levels of cholesterol, low density lipoprotein, and triglycerides, as well as elevated blood pressure, are all believed to be risk factors for development of cardiovascular disease. Increased liver fat is also related to these parameters. These risk factors are particularly prevalent in the elderly, including but not limited to individuals over 65 years of age. Over 40% of individuals over 65 years of age that are screened have been found to have elevated cholesterol levels, and high blood pressure is believed to occur in more than 65% of individuals over 65 and close to 80% of those over 75. Occurrence of elevated triglyceride concentrations in the elderly is equally common, and over 50% of the elderly have elevated liver fat. It is therefore desirable to address these prevalent and morbid health problems, in the elderly and in the general affiliated population.
Generally, lowering plasma levels of LDL cholesterol and TG via lifestyle and pharmacologic means has been positively associated with improvements in both morbidity and mortality from cardiovascular disease. Further, a lower fat diet with conversely more protein has been suggested to help prevent athlerosclerotic lesions. However, lifestyle modifications including low-fat diets in conjunction with moderate exercise appear to be difficult to maintain in the modern United States, and the majority of patients are unable to maintain lifestyle changes long-term. Pharmacologic means such as treatments with niacin, fibrates and statins have all been shown to be effective, but are not without side effects. For example, the facial flushing induced by niacin is a major limitation in its use; fibrates cause liver dysfunction and skin rash; and statins are increasingly associated with myopathy. Thus, therapeutic options that are effective, easy to maintain, and have minimal side-effects are desirable to properly address this epidemic of cardiovascular metabolic abnormality. Moreover, current treatment modalities focus on each of these risk factors independently. In order to minimize adverse interactions between treatment modalities and simplify treatment regimens to encourage patient compliance, it is desirable for one treatment to address multiple facets of cardiovascular health.
More specific aspects of current treatments also have room for improvement. Triglyceride metabolism is believed to involve multiple tissues within the body and has several aspects. Initially, fat is absorbed via the gut and secreted into the splanchnic bloodstream in the form of chylomicrons. Chylomicrons are high in TGs and have the apolipoproteins ApoB-48, ApoCII and ApoE. Chylomicrons are circulated to peripheral tissues, and the TGs are there broken down into free fatty acid (FFA) and glycerol via lipoprotein lipase (LPL). The chylomicron remnants have low levels of TG and increased concentrations of cholesterol, and are transported to the liver. Glycerol and FFA released by the lipoprotein lipase may also be absorbed by the liver. In the liver, TGs and FFAs have several fates. In the fasted state, they can be oxidized to produce ATP or released as an energy source for other tissues. Alternatively, in the fed state, Acyl-CoA can be reesterified into TGs, which are then either stored within hepatocytes, or secreted in the bloodstream alone or as part of VLDL. VLDL has ApoB-100 protein on the surface and once in circulation, VLDL gains the proteins ApoE and ApoCIII from HDL particles and travels to peripheral tissues, where, like chylomicron, TGs are extracted via lipoprotein lipase. As the TG concentration decreases and the cholesterol proportion increases, the lipids turn into LDL.
There are believed to be multiple sites of regulation of TG metabolism. ApoCIII has been shown to inhibit hepatic lipase and inhibit the interaction of TG with hepatic lipoprotein receptors. ApoCIII is thought to increase TG in the plasma of the blood by decreasing peripheral clearance via inhibition of LPL. ApoCII is believed to increase the peripheral clearance of TG's by simulating LPL. Both ApoCII and ApoCIII concentrations and synthetic rates have been closely tied to plasma TG concentrations in healthy patients and those with hyperlipidemia.
Several of these sites of regulation have been targeted by different drugs. Several drugs are currently used to block the initial absorption of TG and cholesterol via the gut, such as eztembamide. Nicotinic acid, or niacin, is believed to work via binding to HM74 receptors in adipose tissue, and via cAMP causes a reduced association of hormone sensitive lipase (HSL) with lipid droplets in adipose tissue, thus causing a decrease in FFA release from adipose tissue. Other drugs, such as the PPAR agonist fibrates, are thought to increase the oxidation of fats within mitochondria and peroxisomes, and thus decrease the hepatic output of TG. Further, they increase plasma clearance by increasing ApoCII expression and activity and decreasing the expression of ApoCIII. They also are believed to increase the expression of APoA, a protein specific to HDL, and thus have been demonstrated to induce moderate increases in HDL concentrations. Statins are believed to work by inhibiting HmgCoase within the liver, and decreasing the de novo synthesis of cholesterol.
Fibrates are believed to have a slightly greater efficacy in terms of lowering plasma TGs compared to statins, although the percent change depends on the population being treated. It has been shown, in elderly patients with normotryglyceridemia, that fenofibrate treatment decreased plasma TGs within 10 days of treatment. In patients with mixed hyperlipidemia, 80 mg of atorvostatin daily were shown to reduce TGs by 65% and VLDL by 57% whereas 200 mg of fenofibrate decreased TGs and VLDL by 57% and 64%, respectively. Patients with type 2 diabetes mellitus (T2DM) were shown to experience a 27% decrease in plasma TGs following 3 months of fenofibrate therapy. Adults with hypertryglyceridemia were shown to experience a 46% decrease in post-paradial TGs after fenofibrate treatment. After treatment with the fibrate gemfibrozil, TG concentrations were shown to decrease by 38% in patients with isolated hypercholesterolemia and 45% in patients with hypertryglyceridemia and hypercholesterolemia; the maximal effects were seen within 4 weeks of treatments. Based on these studies, it appears that in patients with hypertryglyceridemia, the extent of decrease is greater than patients with normotryglyceridemia and can be expected to range from about 25-60%. The goal of a nutritional supplement is to achieve comparable or better results without negative side effects.
Fibrate treatments including fenofibrate (a prescription drug) commonly induce the undesirable side effect of liver toxicity. It is therefore desirable to achieve similar or improved efficacy of fibrates without such side effects. The effects of a composition of essential amino acids (EAAs) (i.e., those that cannot be synthesized by the body) and arginine was compared to the effect of fenofibrate in a similar population of elderly. In contrast to the EAA+arginine, fenofibrate treatment for 60 days had no significant effect on liver triglyceride. Plasma triglyceride concentration fell approximately 33%, as compared to the 20% reduction in those receiving EAAs+arginine. These results are shown in FIG. 2. Due to these positive effects in the absence of negative side effects, it is desirable for a composition for improving cardiovascular health to comprise EEAs.
Alternatively or in addition to pharmaceutic interventions, isocaloric diets with excess protein may improve plasma TGs to the same extent as PPAR agonists and statins. A diet consisting of 22% protein was shown to significantly lower plasma TGs by 32% after 4 weeks, compared to a diet of 12% protein. When patients with T2DM switched 15-30% of their calories from carbohydrates to protein, fasted TG was shown to decrease by 22%, and post-parandial glucose decreased, but cholesterol levels did not change. Plasma TGs were reduced by 23±5% following a high protein diet in patients with pre-existing hypercholesterolemia. However, when elderly patients with poorly controlled T2DM ingested 8 g/day of a mix of 11 amino acids, they were shown to experience significant decreases in post-parandial glucose, hemoglobin A1C, insulin and insulin resistance, but had no changes in plasma lipid parameters. Patients with T2DM were instructed to follow a 30% protein diet rather than a 15% protein diet and at 8 weeks, and were found to have no changes in lipid measurements or glucose control. An epidemiological (rather than biochemical) study of protein intakes effect on cardiovascular health, the Nurses Health Study, tracked over 80,000 women aged 34 to 59 years for 14 years and showed a moderate correlation between the level of protein intake and the occurrence of ischemic heart disease. Data also indicates that higher levels of protein intake have protective effects on elevated blood pressure. A variety of epidemiological studies indicate an inverse relationship between protein intake and blood pressure. It is therefore desirable for a composition for improving cardiovascular health to increase the patient's protein intake.
The mechanism by which protein alters plasma triglyceride concentrations is unclear. Current theories are shown in FIG. 1. It is believed to take approximately 3 weeks for plasma lipids to be altered following the initiation of a high protein diet. LPL is believed to be crucial to the regulation of plasma triglyceride, and may be altered by activity levels and diet. A diet high in fats and/or saturated fat is believed to depress LPL activity in adipose tissue and increase LPL activity in muscle tissue. Exercise has also been show to increase LPL activity. ApoCII transcription is believed to be regulated by PPAR-α and thyroid response element gene domains on chromosome 19. These genes are believed to be stimulated by alteration in bile acids (including chenodeoxycholic, deoxycholic, and lithocolic acid concentrations) PPAR-α agonists, and thyroid hormone, and down-regulated by human ApoA-1 regulatory protein. Current medications that stimulate the thyroid response element (TRE) are believed to significantly lower plasma TG and cholesterol in rats. Protein likely does not alter the gut absorption of triglyceride, since the effects of a high protein diet are believed to be additive to those of the fat binding resin cholestyramine. It may also be that protein supplementation alters the secretion of TGs from the liver, although the likely mechanism may be the reduction of carbohydrates in the diet. A high protein diet in Zucker rats decreased hepatic VLDL secretion, although so does a high fat diet. Obese Zucker rats had a several fold increase in the incorporation of both protein and palmitate into VLDL particles, indicating that the synthetic function of both were increased in obesity. A diet high in carbohydrate increases plasma levels of ApoCIII, leading to decreased plasma TG clearance. A high carbohydrate diet also increases ApoCII concentrations, and thus alters the ratio between the ApoCIII and ApoCII.
The mechanism responsible for an effect of protein intake on lowering blood pressure is believed to be at least in part due to the extra intake of arginine. Blood pressure is influenced by the diameter of blood vessels, which is partially controlled by nitric oxide (NO). Substances that can alter the production of NO have been shown to lower blood pressure. Arginine supplementation enhances NO synthesis, reduced oxidative stress and modulation of renal hemodynamics, among others. When arginine is administered to hypertensive or healthy humans, in causes vasodilatation and decreased blood pressure. It is therefore desirable for a composition to improve cardiovascular health to include arginine, in order to decrease blood pressure.
This decrease in plasma lipids profiles associated with a high protein diet may be due to the decreased content of carbohydrate. 3 weeks of a diet high in carbohydrates rather than fat induced significant increases in plasma TG, due to increased hepatic de novo synthesis of TG. The increase in plasma TG following a high carbohydrate diet is rapid, with changes seen with 4 days of diet alteration. Further, plasma TG decreased after either a high fat or a high protein diet, as compared to a high carbohydrate diet. This substitution of substrate source is not restricted to dietary substitution: peritoneal dialysis patients receiving a 1.1% solution of amino acids instead of all glucose were shown to experience a 13% decrease in plasma TGs within 1 month of the solution change. Other studies have found similar results over 3 years of treatment.
Because carbohydrate intake is thus believed to induce increases in blood lipids in individuals with preexistent elevations, it is desirable for a composition for improving cardiovascular health to have minimal carbohydrates. This is especially desirable for elderly individuals who are often insulin resistant and cannot obtain nutrition from carbohydrates. Medium chain triglycerides are believed to be particularly suitable for this purpose, as they can be readily oxidized for energy and do not require the hormone insulin to be taken up by tissues. Long chain fatty acids commonly found in food require an enzyme system (carnitinepalmitoyltransferase) to transport the fatty acid into the mitochondria for oxidation. Medium chain triglycerides bypass this step because medium chain fatty acids can diffuse directly into the mitochondria. Therefore, such medium chain fatty acids can provide energy without the concomitant detrimental effect on blood lipids induced by carbohydrate intake. This is of benefit to individuals such as the elderly with insulin resistance, since insulin sensitivity is not required for metabolism of medium chain triglycerides.
The mechanism by which carbohydrate levels influence cardiovascular health remains under study. Carbohydrate intake stimulates ApoA-1, which may play a role in the appearance of increased TG following a high carbohydrate diet. Diets high in carbohydrate are believed to increase the proportion of bile cholesterol, and disrupt the balance between bile acids and cholesterol.
Increasing the proportion of plant sterols in the diet also has been associated with decreased cardiovascular disease. Plant sterols, or phytosterols, are found in cellular membranes of numerous plants, and include steroids with a hydroxyl group in the three-position of the A-ring. Sterols are long chain fatty acid esters and are believed to bind cholesterol in the gut effectively in the gut and prevent its absorption. The three sterols believed to be the most effective in lowering plasma cholesterol are B-sitosterol, campesterol, and stigmasterol. A meta-analysis of multiple studies with plant sterols found that chronic consumption decreased LDL by approximately 0.33-0.50 mmol/L, or a 8-13% decrease, and that this decrease is the equivalent of a 20-25% decrease in cardiovascular disease. Dose response curves appear to be linear, with the minimal effective dose of 1.5 g a day inducing a 10% decrease in total cholesterol. Based on such findings, the National Cholesterol Education Program Adult Treatment Panel has recommended a trial of 2 g a day of plant sterols in patients with hypercholesterolemia, prior to initiation of medical treatment.
Plant sterols are thought to work by decreasing intestinal cholesterol absorption. Plant sterols have been shown to be as effective in lowering cholesterol as starting doses of first generation statins. FIG. 3 shows the response of blood lipids to various doses of phytosterols (e.g., PHYTROL® (a cholesterol-lowering agent). Importantly, the effect of phytosterols is believed to be pronounced on cholesterol, which the EAA+arginine mixture did not significantly affect. On the other hand, phytosterols are not believed to affect plasma triglycerides, which EAAs+arginine is believed to do. It is therefore desirable for a combination to lower cholesterol, the LDL/HDL ratio, triglycerides, and liver triglyceride, as a combination of EAA+arginine and phytosterols is believed to do.
A ratio of sterols to stanols have been shown to lower LDL while raising HDL more effectively than stanols alone, due to the stanols' shorter chain lengths. A sterols to stanols ratio of 2:1 yields more effective cholesterol lowering (up to 8% greater). Additionally, the balanced use of sterols and stanols presents a more functional ingredient which is less waxing and able to be used in non-fat food matrices.
In a manner similar to phytosterols, isoflavones decrease total cholesterol as well as LDL cholesterol. Isoflavones may also be referred to as 3-phenyl-4H-1-benzopyr-4-one, and may have added functional groups. As in the case of the EAAs+arginine, the effect of isoflavones is greater in those with initially elevated values. This is shown in FIG. 4. It is therefore desirable for a composition for improving cardiovascular health to comprise isoflavones.